[unreadable] Psoriasis is a common, inflammatory disease of the skin characterized by hyperproliferation of keratinocytes. A variety of antipsoriatic therapies are available, however, due to problems with side effects and variability in clinical response, intense clinical and commercial interest remains in the development of new treatments. In the current studies, we will investigate the antipsoriatic potential of topically administered thiazolidinediones, a novel class of drugs, which have been shown to inhibit the proliferation of a variety of cell types including keratinocytes. These drugs have been shown to have antipsoriatic effects when administered orally, however, the antipsoriatic effects of topically administered thiazolidinediones are unknown. Therefore, we will determine whether topically administered thiazolidinediones can ameliorate the histologic abnormalities of psoriatic skin in a well-characterized animal model of psoriasis. We will further investigate the antipsoriatic potential of a novel, extremely potent thiazolidinedione recently developed by Bethesda Pharmaceuticals. Finally, we will investigate the mechanisms of the antipsoriatic action of thiazolidinediones by examining their effects on key signaling pathways involved in the growth and differentiation of keratinocytes. If we find that topical administration of thiazolidinediones can promote the more orderly epidermal differentiation of psoriatic skin in vitro and in an animal model of psoriasis, these experiments will motivate Phase II STTR studies of: 1) the antipsoriatic effects of topically administered thiazolidinediones in humans and 2) the antipsoriatic effects of novel and extremely potent thiazolidinediones currently under development by Bethesda Pharmaceuticals for topical therapeutic purposes. [unreadable] [unreadable]